Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecula

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Philos Trans R Soc Lond B Biol Sci. 2007 Jun 29;362(1482):959-71.
of acute promyelocytic leukaemia with all-trans retinoic acid and
arsenic trioxide: a paradigm of synergistic molecular targeting therapy.

Zhou GB, Zhang J, Wang ZY, Chen SJ, Chen Z.
Key Laboratory of Medical Genomics, Shanghai Institute of Hematology,
Ruijin Hospital Affiliated to Shanghai JiaoTong University School of
Medicine (SJTUSM), 197, Ruijin Road II, Shanghai 200025, People's
Republic of China.

To turn a disease
from highly fatal to highly curable is extremely difficult, especially
when the disease is a type of cancer. However, we can gain some insight
into how this can be done by looking back over the 50-year history of
taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute
myeloid leukaemia characterized by an accumulation of abnormal
promyelocytes in bone marrow, a severe bleeding tendency and the
presence of the chromosomal translocation t(15;17) or variants. APL was
considered the most fatal type of acute leukaemia five decades ago and
the treatment of APL was a nightmare for physicians. Great efforts have
been made by scientists worldwide to conquer this disease. The first
use of chemotherapy (CT) was unsuccessful due to lack of supportive
care and cytotoxic-agent-related exacerbated coagulopathy. The first
breakthrough came from the use of anthracyclines which improved the
complete remission (CR) rate, though the 5-year overall survival could
only be attained in a small proportion of patients. A rational and
intriguing hypothesis, to induce differentiation of APL cells rather
than killing them, was raised in the 1970s. Laudably, the use of
all-trans retinoic acid (ATRA) in treating APL resulted in terminal
differentiation of APL cells and a 90-95% CR rate of patients, turning
differentiation therapy in cancer treatment from hypothesis to
practice. The combination of ATRA with CT further improved the 5-year
overall survival. When arsenic trioxide (ATO) was used to treat
relapsed APL not only the patients but also the ancient drug were
revived. ATO exerts dose-dependent dual effects on APL cells: at low
concentration, ATO induces partial differentiation, while at relatively
high concentration, it triggers apoptosis. Of note, both ATRA and ATO
trigger catabolism of the PML-RARalpha fusion protein which is the key
player in APL leukaemogenesis generated from t(15;17), targeting the
RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia
(PML) moieties, respectively. Hence, in treating APL both ATRA and ATO
represent paradigms for molecularly targeted therapy. At molecular
level, ATRA and ATO synergistically modulate multiple downstream
pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript
in an earlier and more thorough manner, and a higher quality remission
and survival in newly diagnosed APL are achieved when ATRA is combined
with ATO, as compared to either monotherapy, making APL a curable
disease. Thus, the story of APL can serve as a model for the
development of curative approaches for disease; it suggests that
molecularly synergistic targeted therapies are powerful tools in
cancer, and dissection of disease pathogenesis or anatomy of the cancer
genome is critical in developing molecular target-based therapies.